As a result of declining fertility and increasing life expectancy, the 21st century will continue to witness the remarkable increase in the number and proportion of older persons that began in the last century. By 2030, more than 70 million Americans, about one in five, will be over age 65. The aging of the population has wide ranging health-related consequences as older persons are at risk for a number of chronic conditions, especially cognitive decline and dementia, that impair their ability to function optimally in the community, reduce wellbeing for both the individuals and their families, and are associated with significant health care costs that must be borne by individuals, their families, and society at large. The overall goal of the proposed project is to explore the role of the epigenome in modulating the effect of life experiences on cognition and dementia in older persons. The proposed study is motivated, in large part, from our work with two large, longitudinal studies of aging and dementia over the past 15 years. We have found that while cognitive decline in old age often results from one or more of three common brain diseases (i.e., Alzheimer's disease, cerebrovascular disease, and Lewy body disease), these conditions only account for about 20% of the variance of cognition in older persons. Thus, factors other than neuropathology must make important contributions to cognitive function in old age. Over the past decade, our group has identified a wide range of life experiences that affect an individual's adult cognitive function but are not involved in the development of known age-related neuropathologic processes, including indices of socioeconomic status, psychological distress, and life activities. A burgeoning literature suggests that the brain may use epigenetic marks as a means of linking these kinds of experiential factors to stable behavioral changes including long term memory storage. Building on our prior work, we propose to conduct epigenome-wide DNA methylation scans on brain tissue from participants in an Exploratory Cohort consisting of the Rush Memory and Aging Project (R01AG17917) and a Confirmatory Cohort consisting of the Religious Orders Study (P30AG10161;R01AG15819). The results of these epigenome-wide scans will be used in a programmatic series of analyses to explore the relation of epigenetic marks to age-related cognitive decline and dementia. The convergence of findings from these two sets of analyses on both cohorts will point to potential DNA methylation sites linking life experiences to cognitive decline and dementia. In additional analyses, we will take advantage of available genome-wide genotyping data on these subjects to examine the interaction between genetic variation and epigenetic marks on cognition and life experiences. In a substudy, we will examine the epigenome wide DNA methylation and histone acetylation from multiple brain regions and on peripheral blood lymphocytes over time. Finally, in secondary analyses, we will examine the relation of epigenetic marks to quantitative measures of the pathologic burden of the three most common causes of cognitive decline and dementia in old age. Together, this integrative proposal represents a timely, novel and powerful approach that will transform our understanding of epigenetic contributions to age-related loss of cognition and dementia in humans. We are not aware of any other studies of older men and women of comparable size, relevant life experiences, clinical data, and follow-up and autopsy rates, in which these analyses can be performed. Thus, the project is well positioned to create a new paradigm for studying age- related cognitive decline and dementia that will lay the groundwork for a wide range of potential interventions that are truly distinct from approaches currently under investigation. Public Health Relevance: Cognitive decline and dementia represent a large and growing public health problem. Disease prevention provides the best long-term strategy to reduce the human and economic toll of disease. Thus, the identification of epigenetic marks that link experiential factors with cognitive decline and dementia could provide important clues for the treatment and prevention of a common and devastating problem of old age. The proposed study to identify novel epigenetic marks associated with risk of dementia is a timely and important study that could provide new knowledge critical to public health.